Abstract

Background

Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies.
T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has
been shown to exert neuroprotective and anti-inflammatory properties in the brain.

Methods

Here we investigate potential sources of GLP-1 in the CNS and the effect of diabetic
conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line
BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR,
immunofluorescence and ELISA.

Results

We show evidence for microglia as a central source of GLP-1 secretion. Furthermore,
we observed that expression and secretion are stimulated by cAMP and dependent on
microglial activation state. We also show that insulin-resistant conditions reduce
the central mRNA expression of proglucagon.

Conclusion

The findings that microglial mRNA expression of proglucagon and GLP-1 protein expression
are affected by high levels of free fatty acids and that both mRNA expression levels
of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli
could be of pathogenic importance for the premature neurodegeneration and cognitive
decline commonly seen in T2D patients, and they may also be harnessed to advantage
in therapeutic efforts to prevent or treat such disorders.